Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia

Abstract

Objective. Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is often present in diabetic (DB) patients. Both conditions are associated with endothelial dysfunction and cardiovascular disease. We hypothesized that diabetic endothelial dysfunction is further compromised by CIH. Methods. Adult male diabetic (BKS.Cg-Dock7 m +/+ Lepr db/J) (db/db) mice (10 weeks old) and their heterozygote littermates were subjected to CIH or intermittent air (IA) for 8 weeks. Mice were separated into 4 groups: IA (intermittent air nondiabetic), IH (intermittent hypoxia nondiabetic), IADB (intermittent air diabetic), and IHDB (intermittent hypoxia diabetic) groups. Endothelium-dependent and endothelium-independent relaxation and modulation by basal nitric oxide (NO) were analyzed using wire myograph. Plasma 8-isoprostane, interleukin-6 (IL-6), and asymmetric dimethylarginine (ADMA) were measured using ELISA. Uncoupling of eNOS was measured using dihydroethidium (DHE) staining. Results. Endothelium-dependent vasodilation and basal NO production were significantly impaired in the IH and IADB group compared to IA group but was more pronounced in IHDB group. Levels of 8-isoprostane, IL-6, ADMA, and eNOS uncoupling were ≈2-fold higher in IH and IADB groups and were further increased in the IHDB group. Conclusion. Endothelial dysfunction is more pronounced in diabetic mice subjected to CIH compared to diabetic or CIH mice alone. Oxidative stress, ADMA, and eNOS uncoupling were exacerbated by CIH in diabetic mice.

Gestational intermittent hypoxia induces endothelial dysfunction, reduces perivascular adiponectin and causes epigenetic changes in adult male offspring

“…For endothelium‐dependent relaxation, aortic rings were constricted with a submaximal dose of phenylephrine (Ph, 1 µ m ; Sigma, St Louis, MO, USA) followed by cumulative additions of ACh (10 −9 to 10 −5 m ; Sigma) (Badran et al . ). For anti‐contractile studies of PVAT, cumulative concentration‐response curves to the constrictor effects of U46619 (9,11‐dideoxy‐9a,11 a‐methanoepoxy prostaglandin F 2a ; Cayman Chemicals, ANN Arbor, MI, USA) (10 −9 to 10 −5 m ) were made.…”

“…Blood vessels were stretched to their optimum tension (5.5 mN) and allowed to equilibrate for 30 min before constriction with 80 mM potassium chloride solution (a solution of 80 mM KCl was prepared by equimolar replacement of NaCl in PSS) and then washing with PSS to return to resting tension. For endothelium-dependent relaxation, aortic rings were constricted with a submaximal dose of phenylephrine (Ph, 1 µM; Sigma, St Louis, MO, USA) followed by cumulative additions of ACh (10 −9 to 10 −5 M; Sigma) (Badran et al 2016). For anti-contractile studies of PVAT, cumulative concentration-response curves to the constrictor effects of U46619 (9,11-dideoxy-9a,11 a-methanoepoxy prostaglandin F 2a ; Cayman Chemicals, ANN Arbor, MI, USA) (10 −9 to 10 −5 M) were made.…”

The Bidirectional Relationship Between Obstructive Sleep Apnea and Metabolic Disease

“…As many patients lose weight with CPAP, noting changes in body fat specifically ( 174 ), is particularly important to consider when reflecting on leptin action. When exposed to IH, rodents with deficient leptin signaling have exacerbated insulin resistance ( 175 ) and increased cardiovascular impairments including endothelial dysfunction ( 176 ). Leptin treatment prior to IH reduces insulin resistance and hyperlipidemia and improves endothelial relaxation and vascular stiffness in ob/ob mice ( 175 , 177 ).…”

Taking up the cudgels for the traditional reactive oxygen and nitrogen species detection assays and their use in the cardiovascular system

“…Likewise, incubation of the cryo sections from sleep apnea patients with L-NAME decreased endothelial superoxide formation and nitric oxide levels more efficiently in the diseased group with only minor changes upon CPAP. Laher and coworkers reported similar impairment of endothelial function (measured by acetylcholine-dependent relaxation) by intermittent hypoxia and diabetes with a dramatic aggravation when both risk factors were present [75]. These functional data were well correlated by a similar degree of eNOS uncoupling (measured by endothelial DHE cryo staining) intermittent hypoxia or diabetes groups with a substantial further increase in the presence of both risk factors.…”